Genotype 3 is associated with rapid histological progression in chronic HCV infection

While several risk factors for the histological progression of chronic hepatitis C have been identified, the contribution of HCV genotypes to liver fibrosis evolution remains controversial. The aim of the present study was to assess independent predictors for fibrosis progression. Methods: We identified 1540 patients from the Swiss Hepatitis C Cohort database with at least one liver biopsy prior to antiviral treatment. Factors associated with fibrosis stage, steatosis and histological activity were assessed in univariate and multivariate regression models. Fibrosis progression rate per year was calculated in a subgroup of 1263 patients, in whom risk factors were assessed by cumulative incidence curves, logistic and linear regression models. Results: Independent risk factors for rapid fibrosis progression included male sex (OR = 1.66, 95% CI 1.25-2.21, P <0.001), age at infection (OR = 1.08, 95% CI 1.06-1.10, P <0.001), histological activity (OR = 2.14, 95% CI 1.61-2.85, P <0.001) and genotype 3 (OR = 1.97, 95% CI 1.43-2.72, P <0.001). Genotype 2 was associated with slow progression (OR = 0.51, 95% CI 0.30-0.89, P = 0.02), but this observation may be due to the decreased prevalence of genotype 2 over the last decades, leading to an overrepresentation of subjects with genotype 2 with a slow progression rate. Conclusion: This study shows a significant association of genotype 3 with accelerated fibrosis. While assessing risk factors for fibrosis progression, the changing epidemiology of HCV genotypes over time needs to be taken into account.

Plasma Level of Mmp-9 as Predictive Factor for Response and Progression Free Survival in Patients Treated with Bevacizumab (Bev) and Pegylated Liposomal Doxorubicin (Pld): Sakk 24/06

Background: There is currently no identified marker predicting benefit from Bev in patients with breast cancer (pts). We monitored prospectively 6 angiogenesis-related factors in the blood of advanced stage pts treated with a combination of Bev and PLD in a phase II trial of the Swiss Group for Clinical Cancer Research, SAKK.Methods: Pts received PLD (20 mg/m2) and Bev (10 mg/kg) every 2 weeks for a maximum of 12 administrations, followed by Bev monotherapy until progression or severe toxicity. Blood samples were collected at baseline, during treatment and at treatment discontinuation. Enzyme-linked immunosorbent assays (Quantikine, R&DSystems and Reliatech) were used to measure vascular endothelial growth factor (VEGF), placental growth factor (PlGF), matrix metalloproteinase 9 (MMP-9) and soluble VEGF receptors -1, -2 and -3. The natural log-transformed (ln) data for each factor was analyzed by analysis of variance (ANOVA) model to investigate differences between the mean values of the subgroups of interest (where a = 0.05), based on the best tumor response by RECIST.Results: 132 samples were collected in 41 pts. The mean of baseline ln MMP-9 levels was significantly lower in pts with tumor progression than those with tumor response (p=0.0202, log fold change=0.8786) or disease control (p=0.0035, log fold change=0.8427). Higher MMP-9 level was a significant predictor of superior progression free survival (PFS): p=0.0417, hazard ratio=0.574, 95% CI=0.336-0.979. In a multivariate cox proportional hazards model, containing performance status, disease free interval, number of tumor sites, visceral involvement and prior adjuvant chemotherapy, using stepwise regression baseline MMP-9 was still a statistically 117P Table 1. SOLTI-0701* AC01B07* NU07B1* SOR+CAP N=20 PL+CAP N=33 SOR+ GEM/CAP N=23 PL+ GEM/CAP N=27 SOR+PAC N=48 PL+PAC N=46 Baseline characteristics Age, median (range), y 49 (32-72) 53 (30-78 54 (32-69) 57 (31-82) 50 (27-80) 52 (23-74) AJCC stage, n (%) IIIB/IIIC 3 (15) 6 (18) 0 (0) 3 (11) 8 (17) 9 (20) IV 17 (85) 27 (82) 23 (100) 24 (89) 40 (83) 37 (80) Metastatic site, n (%) Non-visceral 3 (15) 6 (18) 7 (30) 6 (22) 9 (19) 17 (37) Visceral 17 (85) 27 (82) 16 (70) 21 (78) 39 (81) 29 (63) Prior metastatic chemo, n (%) 8 (40) 15 (45) 21 (91) 25 (93) - - Efficacy PFS, median, mo 4.3 2.5 3.1 2.6 5.6 5.5 HR (95% CI)_ 0.60 (0.31, 1.14) 0.57 (0.30, 1.09) 0.86 (0.50, 1.45) 1-sided P value_ 0.055 0.044 0.281 Overall survival, median, mo 17.5 16.1 Pending 14.7 18.2 HR (95% CI)_ 0.98 (0.50, 1.89) 1.11 (0.64, 1.94) 1-sided P value_ 0.476 0.352 Safety N=20 N=33 N=22 N=27 N=46 N=46 Tx-emergent Grade 3/4, n (%) 15 (75) 16 (48) 20 (91) 17 (63) 36 (78) 16 (35) Grade 3§ hand-foot skin reaction/ syndrome 8 (40) 5 (15) 8 (36) 0 (0) 14 (30) 2 (4) *Efficacy results based on intent-to-treat population and safety results based on safety population (pts who received study drug[s]); _Cox regression within each subgroup; _log-rank test within each subgroup; §maximum toxicity grade for hand-foot skin reaction/syndrome; AJCC, American Joint Committee on Cancer mittedabstractsª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com Downloaded from annonc.oxfordjournals.org at Bibliotheque Cantonale et Universitaire on June 6, 2011 significant factor (p=0.0266). The results of the other measured factors were presented elsewhere.Conclusions: Higher levels of MMP-9 could predict tumor response and superior PFSin pts treated with a combination of Bev and PLD. These exploratory results justify further investigations of MMP-9 in pts treated with Bev combinations in order to assess its role as a prognostic and predictive factor.Disclosure: K. Zaman: Participation in advisory board of Roche; partial sponsoring ofthe study by Roche (the main sponsor was the Swiss Federation against Cancer (Oncosuisse)). B. Thu¨rlimann: stock of Roche; Research grants from Roche. R. vonMoos: Participant of Advisory Board and Speaker honoraria

Variation d'expression des récepteurs hormonaux et d'HER-2 dans l'évolution du cancer du sein : quelles implications en pratique clinique [Hormone receptors and HER-2 changes during breast cancer progression: clinical implications].

Breast cancer remains a major public health problem. Even if there is an increase in this cancer curability, metastatic breast cancer remains a lethal disease in the vast majority of cases. Therapeutic advances in the chemotherapeutic and targeted therapies fields induced an increase in survival, however the proportion of long survivors remains low. Phenotypic instability, an early process initiated during tumour progression, and continued on the metastatic stage of the disease, can be one of the putative hypotheses explaining these results. An increasing amount of scientific data are pledging for a reanalysis of the phenotypic profile regarding hormone receptors and HER-2 status of metastatic lesions in order to identify drugable targets and allow individualisation of the treatment of these metastatic breast cancer patients. Phenotypic changes between the primary tumour and the paired metastatic lymph nodes are a challenging pitfall, raising the question of which site has to be assessed in the adjuvant treatment decision process. This article presents a comprehensive analysis of the frequency of theses phenotypic changes altogether with new modalities to evaluate this phenotypic status.

Effects of unilateral motor cortex lesion on ipsilesional hand's reach and grasp performance in monkeys: relationship with recovery in the contralesional hand.

Manual dexterity, a prerogative of primates, is under the control of the corticospinal (CS) tract. Because 90-95% of CS axons decussate, it is assumed that this control is exerted essentially on the contralateral hand. Consistently, unilateral lesion of the hand representation in the motor cortex is followed by a complete loss of dexterity of the contralesional hand. During the months following lesion, spontaneous recovery of manual dexterity takes place to a highly variable extent across subjects, although largely incomplete. In the present study, we tested the hypothesis that after a significant postlesion period, manual performance in the ipsilesional hand is correlated with the extent of functional recovery in the contralesional hand. To this aim, ten adult macaque monkeys were subjected to permanent unilateral motor cortex lesion. Monkeys' manual performance was assessed for each hand during several months postlesion, using our standard behavioral test (modified Brinkman board task) that provides a quantitative measure of reach and grasp ability. The ipsilesional hand's performance was found to be significantly enhanced over the long term (100-300 days postlesion) in six of ten monkeys, with the six exhibiting the best, though incomplete, recovery of the contralesional hand. There was a statistically significant correlation (r = 0.932; P < 0.001) between performance in the ipsilesional hand after significant postlesion period and the extent of recovery of the contralesional hand. This observation is interpreted in terms of different possible mechanisms of recovery, dependent on the recruitment of motor areas in the lesioned and/or intact hemispheres.

MMP-9 as predictive factor for response and progression free survival in breast cancer patients treated with bevacizumab and pegylated liposomal doxorubicin. A multicenter, single-arm phase II trial (SAKK24/06). On behalf of the Swiss Group for Clinical Cancer Research (SAKK).

The benefit of bevacizumab (Bv) has been shown in different tumors including colorectal cancer, renal cancer, pulmonary non-small cell cancer and also breast cancer. However to date, there is no established test evaluating the angiogenic status of a patient and monitoring the effects of anti-angiogenic treatments. Tumor angiogenesis is the result of a balance between multiple pro- and anti¬angiogenic molecules. There is very little published clinical data exploring the impact of the anti-angiogenic therapy on the different angiogenesis-related molecules and the potential role of these molecules as prognostic or predictive factors.

Altered expression of CD44 and DKK1 in the progression of Barrett's esophagus to esophageal adenocarcinoma.

Barrett's esophagus (BE) is an acquired condition in which the normal lining of the esophagus is replaced by intestinal metaplastic epithelium. BE can evolve to esophageal adenocarcinoma (EAC) through low-grade dysplasia (LGD) and high-grade dysplasia (HGD). The only generally accepted marker for increased risk of EAC is the presence of HGD, diagnosed on endoscopic biopsies. More specific markers for the prediction of EAC risk are needed. A tissue microarray was constructed comprising tissue samples from BE, LGD, HGD, and EAC. Marker expression was studied by immunohistochemistry using antibodies against CD44, DKK1, CDX2, COX2, SOX9, OCT1, E-cadherin, and beta-catenin. Immunostaining was evaluated semi-quantitatively. CD44 expression decreased in HGD and EAC relative to BE and LGD. DKK1 expression increased in HGD and EAC relative to BE and LDG. CDX2 expression increased in HGD but decreased in EAC. COX2 expression decreased in EAC, and SOX9 expression increased only in the upper crypt epithelial cells in HGD. E-cadherin expression decreased in EAC. Nuclear beta-catenin was not significantly different between BE, LGD, and HGD. Loss of CD44 and gain of DKK1 expression characterizes progression from BE and LGD to HGD and EAC, and their altered expression might indicate an increased risk for developing an EAC. This observation warrants inclusion of these immunohistochemically detectable markers in a study with a long patient follow-up.

Altering in vivo fate of heart-infiltrating progenitors from pro-fibrotic into F4/80+macrophages prevents progression of myocarditis into inflammatory dilated cardiomyopathy

Rationale: Experimental autoimmune myocarditis (EAM) mirrors important pathogenic aspects of inflammatory cardiomyopathy, a common cause of heart failure. In EAM, TGF-β-dependent conversion of heart-infiltrating prominin-1+ progenitors into myofibroblasts is critical for development of fibrosis and the end-stage heart failure phenotype. Therapeutic strategies modulating the in vivo fate of prominin-1+ progenitors might therefore prevent TGF-β-mediated cardiac fibrosis and pathological remodelling. Methods and Results: EAM was induced in BALB/c mice using alpha-myosin heavy chain (aMyHC) peptide/complete Freund's adjuvant (CFA) immunization. Prominin-1+ cells were isolated from the inflamed hearts at day 21 after immunization, expanded and treated with Macrophage Colony-Stimulating Factor (M-CSF) or Transforming Growth Factor-beta (TGF-β). Herein, we demonstrated that M-CSF turns, ex vivo and in the EAM, heart-infiltrating prominin-1+ progenitors into immunosuppressive F4/80/CD11b/CD16/32/NOS2-expressing, nitric oxide producing and E.coli bacteria phygocyting macrophages, and protect further TGF-β-stimulated differentiation into pathogenic myofibroblasts. Systemic M-CSF treatment during myocarditis completely prevented post-inflammatory fibrosis, T cell relapse and left ventricular dysfunction. Mechanistically, M-CSF-induced macrophage differentiation from prominin-1+ progenitors critically required nitric oxide synthase 2. Accordingly, M-CSF treatment failed to reduce myocardial fibrosis development in Nos2-/- mice. Conclusions: Altering the in vivo fate of inflammatory prominin-1 expressing progenitors from pro-fibrotic into the F4/80 expressing macrophage phenotype protects from myocarditis progression, cardiac fibrosis, and heart failure. These findings offer a modern therapeutic model and challenge former concepts, which attributed macrophages a detrimental role in inflammatory cardiomyopathy progression.

Activin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response.

Activin is an important orchestrator of wound repair, but its potential role in skin carcinogenesis has not been addressed. Here we show using different types of genetically modified mice that enhanced levels of activin in the skin promote skin tumour formation and their malignant progression through induction of a pro-tumourigenic microenvironment. This includes accumulation of tumour-promoting Langerhans cells and regulatory T cells in the epidermis. Furthermore, activin inhibits proliferation of tumour-suppressive epidermal γδ T cells, resulting in their progressive loss during tumour promotion. An increase in activin expression was also found in human cutaneous basal and squamous cell carcinomas when compared with control tissue. These findings highlight the parallels between wound healing and cancer, and suggest inhibition of activin action as a promising strategy for the treatment of cancers overexpressing this factor.

Endothelial nitric oxide synthase gene transfer restores endothelium-dependent relaxations and attenuates lesion formation in carotid arteries in apolipoprotein E-deficient mice.

Nitric oxide (NO) and monocyte chemoattractant protein-1 (MCP-1) exert partly opposing effects in vascular biology. NO plays pleiotropic vasoprotective roles including vasodilation and inhibition of platelet aggregation, smooth muscle cell proliferation, and endothelial monocyte adhesion, the last effect being mediated by MCP-1 downregulation. Early stages of arteriosclerosis are associated with reduced NO bioactivity and enhanced MCP-1 expression. We have evaluated adenovirus-mediated gene transfer of human endothelial NO synthase (eNOS) and of a N-terminal deletion (8ND) mutant of the MCP-1 gene that acts as a MCP-1 inhibitor in arteriosclerosis-prone, apolipoprotein E-deficient (ApoE(-/-)) mice. Endothelium-dependent relaxations were impaired in carotid arteries instilled with a noncoding adenoviral vector but were restored by eNOS gene transfer (p < 0.01). A perivascular collar was placed around the common carotid artery to accelerate lesion formation. eNOS gene transfer reduced lesion surface areas, intima/media ratios, and macrophage contents in the media at 5-week follow-up (p < 0.05). In contrast, 8ND-MCP-1 gene transfer did not prevent lesion formation. In conclusion, eNOS gene transfer restores endothelium-dependent vasodilation and inhibits lesion formation in ApoE(-/-) mouse carotids. Further studies are needed to assess whether vasoprotection is maintained at later disease stages and to evaluate the long-term efficacy of eNOS gene therapy for primary arteriosclerosis.

Facteurs Influençant la Progression du Score EDSS dans la Sclérose en Plaques Récurrente-Rémittente

Introduction : la Sclérose en plaques (SEP) est le prototype de désordre auto-immun du système nerveux central. Avec environ 110 malades par 100'000 habitants, la Suisse est considérée un pays à haute prévalence. Chez environ 80% des patients, la maladie débute par la forme récurrente- rémittente (RR), où des poussées aiguës s'intercalent avec des périodes de rémission. Cette phase se conclut dans son évolution naturelle généralement en une phase secondairement progressive, pendant laquelle le déficit progresse en l'absence de poussée. Sur le plan physiopathologique, deux phénomènes interagissent : l'atteinte inflammatoire démyélinisante et l'atteinte neurodégénerative. La première est { l'origine des poussées aiguës, la deuxième se manifeste cliniquement par la progression irréversible du déficit neurologique. En Suisse les immunomodulateurs ont été utilisés comme thérapies de fond pour la SEP à partir des années 1995. Leur effet sur le taux de poussées a été largement démontré, tandis que leur efficacité sur l'évolution de la maladie à long terme reste ouverte. Le moyen le plus répandu pour quantifier le niveau du handicap neurologique est la Kurtzke Expanded Disability Status Scale (EDSS). Cette échelle évalue les troubles neurologiques en les classifiant de 0 (examen normal) à 10 (décès) avec des marches de demi-points. Notre recherche à voulu identifier des facteurs cliniques précoces { valeur prédictif sur l'évolution du déficit neurologique permanent, ainsi qu'analyser le moment d'introduction du traitement pour extraire des informations utiles { la décision thérapeutique. Méthodes : Exploitation de la base de données iMed-CHUV comptant 1150 patients SEP (dont 622 SEP RR) pour analyser rétrospectivement, dans la SEP RR, l'influence de différentes variables cliniques précoces (taux de poussées pendant les premières deux années de maladie, intervalle entre les deux premières poussées, sévérité et site anatomique de la première poussée, déficit résiduel après la première poussée) et de deux caractéristiques liées { l'instauration du traitement immunosuppresseur de fond (âge et délai d'introduction) sur l'évolution du déficit neurologique vers un score EDSS ≥4.0. Les variables ont été testées avec la méthode d'estimation de taux de survie Kaplan-Meier. Résultats: 349 patients avec SEP RR possédaient les critères nécessaires pour faire partie de l'analyse, le suivi moyen étant de 8.26 ans (SD 4.77). Un taux de poussées élevé pendant les premiers 2 ans (>1 vs ≤1) et un long intervalle entre les 2 premiers épisodes (>36 vs >12-36 vs ≤12) étaient significativement associés au risque de progression du déficit neurologique vers un score EDSS de 4.0 ou plus (log Rank P=0.016 et P=0.008 respectivement). Par contre ni le site anatomique de la première poussée ni l'âge d'introduction du traitement immunomodulateur n'avaient d'influence significative sur la progression du déficit neurologique (log rank P=0.370 et P=0.945 respectivement). Etonnamment une introduction rapide du traitement était associée à une plus forte progression du déficit neurologique (log rank P=0.032), montrant qu'une partie des patients a une évolution bénigne même en l'absence de traitement. Conclusions : L'activité inflammatoire précoce, dont le niveau peut être estimé par indices précoces comme le taux de poussées et l'intervalle entre les deux premières poussées, mais non le site de primo-manifestation prédit la progression ultérieure du déficit neurologique. Ces indices doivent être utilisés en combinaison avec les informations fournies par l'IRM pour l'individuation et le traitement précoce des patients à risque, indépendamment de leur âge. En raison des effets indésirables et des coûts élevés, les thérapies doivent cibler de façon spécifique les classes à risque, et épargner les patients avec évolution lente.

Fragment N2, a caspase-3-generated RasGAP fragment, inhibits breast cancer metastatic progression

The p120 RasGAP protein negatively regulates Ras via its GAP domain. RasGAP carries several other domains that modulate several signaling molecules such as Rho. RasGAP is also a caspase-3 substrate. One of the caspase-3-generated RasGAP fragments, corresponding to amino acids 158-455 and called fragment N2, was previously reported to specifically sensitize cancer cells to death induced by various anticancer agents. Here, we show that fragment N2 inhibits migration in vitro and that it impairs metastatic progression of breast cancer to the lung. Hence, stress-activated caspase-3 might contribute to the suppression of metastasis through the generation of fragment N2. These results indicate that the activity borne by fragment N2 has a potential therapeutic relevance to counteract the metastatic process.

The tumour suppressor LATS2 interacts with both Signalosome and E3 ubiquitin ligases : implications in control of cell cycle progression

SUMMARY LATS2 is a member of the Lats tumour suppressor gene family. The human LATS2 gene is located at chromosome 13q11-12, which has been shown to be a hot spot (67%) for LOH in nonsmall cell lung cancer. Both lats mosaic flies and LATS1 deficient mice spontaneously develop tumours, an observation that is explained by the function of LATS1 in suppressing tumourigenesis by negatively regulating cell proliferation by modulating Cdc2/Cyclin A activity. LATS1 also plays a critical role in maintenance of ploidy through its action on the spindle assembly checkpoint. Initial insights into the function of LATS2 reveals that the protein is involved in the G2/M transition of the cell cycle, whereby it controls the phosphorylation status of Cdc25C. The aim of the present study was to identify LATS2 interacting partners that would provide a more thorough understanding of the molecular pathways in which the protein is involved. The yeast two-hybrid system identified a number of candidate genes that interact with LATS2. Most of the interactions were confirmed biochemically by GST-pull down assays that enabled us to demonstrate that LATS2 is an integral component of the Signalosome complex. The Signalosome is thought to be required for the establishment of functional Cullin-based E3 ubiquitin ligases, the substrate-recognition elements of the ubiquitin-mediated protein proteolytic pathway. The findings that LATS2 also interacts with all of the components of the E3 enzymes allows us to postulate that LATS2 is probably involved in the regulation of this Signalosome-E3 super-complex. In addition, the discovery that LATS2 associates with multiple protein kinases localised at the cellular membrane and in various signalling cascades supports the idea that LATS2 functions as an integrator of signals which allows it to monitor the activity of these pathways and translate these signals through its action on the Signalosome. Furthermore, the observation that a kinase-dead LATS2 mutant arrests at the G2/M phase of the cell cycle, demonstrates that the protein, through the action of its kinase domain, is crucial for progression through the cell cycle, an action in accordance to its proposed role as a regulator of E3 ubiquitin ligases. The findings presented herein provide evidence that LATS2 associates with the Signalosome-E3 ubiquitin ligases super-complex which governs protein stability. Any alteration of the protein would have a strong impact on pathways that modulate cell proliferation, as shown by its implication in tumourigenesis. RESUME LATS2 est un membre de la famille de gènes suppresseurs de tumeurs LATS. Le gène humain LATS2 est situé sur le chromosome 13q11-12, une région qui s'est avérée être un point sensible (67%) dans la perte d'hétérozigosité (LOH) notamment pour le cancer du poumon. Le fait que des tumeurs se développent spontanément chez les souris qui sont déficientes pour le gène LATS1 ainsi que dans des cellules mutantes pour LATS chez la Drosophile, est expliqué Par la fonction de LATS1, qui est de supprimer l'apparition de tumeurs en réprimant la prolifération cellulaire à travers sa capacité à réguler l'activité de Cdc2/Cyciine A. LATS1 joue également un rôle important au niveau du maintient de la ploïdie de la cellule, au travers de son action sur les points de contrôle de l'assemblage du fuseau mitotique. Les premières études du gène LATS2 indiquent que la protéine est, par son contrôle des réactions de phosphorylation de la Cdc25C, impliquée dans la transition 021M. Le but de cette étude était d'identifier les protéines qui interagissent avec LATS2, en vue d'obtenir une compréhension plus approfondie des mécanismes moléculaires dans lesquels LATS2 se trouve engagée. Le système de double-hybride chez la levure a permis l'identification d'un grand nombre de gènes qui interagissent avec LATS2. La plupart des interactions ont été confirmées par GST «pull clown», une technique in vitro qui a permis de démontrer que LATS2 est un composant intégral du Signalosome. Ce complexe est supposé réguler l'activité des E3 ubiquitine-rigases, les éléments responsables du recrutement des substrats qui doivent être recyclés par la voie de dégradation ubiquitine-dépendante. Les résultats obtenus indiquent également que LATS2 interagit avec tous les composants des enzymes E3, ce qui nous permet de soumettre l'idée selon laquelle la protéine LATS2 est en fait impliquée dans la régulation du complexe Signalosorne-E3. De plus, la découverte que LATS2 se trouve associée à plusieurs protéines kinases localisées au niveau de la membrane cellulaire, ainsi que dans diverses voies de transduction, confirment l'idée que LATS2 fonctionne en tant que molécule qui intègre les signaux en provenance de ces différentes voies cellulaires. De ce fait, il lui serait possible de coordonner la destruction des protéines au moyen du complexe Signalosome, permettant ainsi de réprimer l'activité des voies de signalisation. En outre, l'introduction d'une mutation dans le domaine kinase de LATS2 résulte en l'arrêt du cycle cellulaire en G2/M, ce qui montre que la protéine, au travers de son domaine kinase, est cruciale pour le bon fonctionnement du cycle cellulaire, ceci en accord avec son rôle proposé comme régulateur des E3 ubiquitine-ligases. Les résultats présentés dans ce manuscrit démontrent que la protéine LATS2 se trouve associée au complexe Signalosome-E3 qui régule la dégradation des protéines. La moindre modification de la protéine engendrerait des répercussions importantes au niveau des voies de transduction qui contrôlent fa prolifération ceilulaire, ce qui atteste du rôle déterminant que joue LAT32 dans la tumorigénèse.